Dyspepsia is a common symptom ranging in prevalence from 26% in the United States to 41% in England (1). Whilst only 1 in 4 patients seek medical help (2) the condition results in significant health care costs (3) and an organic cause is found in only 40% of patients. The Rome criteria for diagnosing idiopathic or nonulcer dyspepsia (NUD) were put forward in 1991 and consist of chronic or recurrent upper abdominal pain or discomfort in the absence of obvious pathology (4). The Rome group suggested subcategorising NUD into ulcer-like, reflux-like, dysmotility-like and non-specific dyspepsia. This classification has been questioned on the grounds that there is a marked overlap of symptoms and an overlap between the symptoms and those of the irritable bowel syndrome (5).
Conventional diagnosne evaluation (endoscopy, ultrasonography, 24 h ambulatory pH monitoring) does not reveal a structural or biochemical abnormality to explain NUD. Attempts at elucidating the pathophysiology of the condition have produced inconsistent findings (6) and a wide array of theories are currently put forward (7).
Serotonin (5HT) is a neurotransmitter both in the enteric nervous system (8) and in the brain (9). It plays a key role in regulating gut physiology, including peristalsis and intestinal tone (10). Animal studies have shown that intracerebroventricular injection of fenfluramine (a serotonin releasing agent) inhibits gastric emptying (11). Selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are widely used in the treatment of depression and produce a transient syndrome similar to NUD in up to 30% of patients treated (I2).
Studies indicate that a central 5HT1a receptor hypersensitivity may be involved in the pathophysiology of NUD (13,14). The release of prolactin from the anterior pituitary is under dopamine inhibition and under 5HT stimulation, probably at the level of the hypothalamus (15). Buspirone is an azaspirodecanedione, which acts as a partial agonist at the 5HT1a receptor (16) and stimulates prolactin release, We have established that prolactin release following buspirone challenge is enhanced in NUD indicating 5HT1a receptor supersensitivity in this condition.
We have demonstrated this in a clinical study that extends our previous findings reported in U.S. Pat. No. 5,403,848.
A total of 109 subjects, 50 NUD patients (39 female/11 male) and 59 healthy comparison subjects (32 female/28 male) gave fully informed consent to take part in the study, which had Ethics Committee approval. The mean±SD age of the patients was 35.6±12.2 years (Range 20-62) and of the comparison group 27.2±7.6 years (Range 20-52). At 0830 h subjects had a cannula inserted in a forearm vein. Buspirone (30mg) or, matching placebo was administered orally at 0900 h (Time 0). Blood was taken at 0, 30, 60, 90, 120 and 180 min. Prolactin levels rose in all subjects challenged with buspirone. The mean±SD AUC in patients was 46±35 and in healthy subjects 24±35. A 2-way repeated measures ANOVA yields a significant group X time interaction with differences significant at 60 min (p<0.05), 90 min (p<0.01) and 120 min (p<0.05). Prolactin concentration at 90 min provided the best discrimination between the two groups.
According to the present invention, what is required to treat non-ulcerative dyspepsia is the administration of effective amounts of a substance that reduces the sensitivity of 5HT1a receptors and we have discovered that pindolol, which has affinity for 5HT1a receptors has beneficial effects in subjects suffering from non-ulcerative dyspepsia.